Lesions associated with atherosclerosis and similar diseases of the vasculature in general have been found to comprise cholesterol, cholesterol ester, phospholipid and triglyceride in one or more lipid phases. Katz, S, and Small, Daniel, J. Biol. Chem., 255(20):9753-59 (1980). The lipophilic nature of the lesions renders them naturally compatible with blood serum lipoproteins such that serum lipoproteins tend to shuttle in and out of the lesions. Exacerbating this effect is the fact that the cells comprising the surface of such lesions generally exhibit the phenomenon known as enhanced permeability and retention (EPR).
The EPR effect, which was first described with regard to the preferential permeation into, and retention by, tumor tissues of serum proteins but which has since been found to extend to many types of diseased tissues including vascular lesions, is the result of defective tissue architecture, changes in permeation mediators and impaired lymphatic drainage. That is, the vascular endothelium of tumors and vascular lesions tends to have relatively large gaps in the endothelial cell-cell junctions compared to normal tissue. This permits larger molecular species to permeate the tissue than is the case for healthy tissue. The altered permeation mediators and impaired lymphatic drainage mechanism assure that the molecules that have penetrated the lesion stay there. The EPR effect has been used in practice to selectively introduce and retain chemotherapeutics in tumors by tethering small molecule drugs to polymers or nanoparticles that are too large to permeate normal tissue but that readily infiltrate tumor tissue.
What would be valuable would be a method of using the affinity of vascular lesions for serum lipoproteins together with the EPR effect to direct, i.e., target, therapeutic agents to the damaged tissue. This invention provides such a method.